Cdk5 regulates pain signaling: We have recently reported a novel role of Cdk5 in pain signaling. We previously reported that expression of Cdk5 and p35, as well as Cdk5 kinase activity, was increased in the dorsal root ganglia (DRG) and the spinal cord (SC) after peripheral inflammation. Inflammation induced by carrageenan injection in the hind paws of mice increased the mRNA and protein levels of Cdk5/p35 in nociceptive neurons, with a subsequent increase in Cdk5 kinase activity. Furthermore, we identified that the elevated Cdk5 activity phosphorylates transient receptor potential vanilloid 1 (TRPV1), a key receptor that modulates agonist-induced calcium influx in neurons. Additionally, we found that inflammation triggers an increase in Cdk5 activity through activation of early growth response 1 (Egr-1) and p35 expression by TNF-alpha. These findings suggest that Cdk5 plays an important role in the molecular mechanisms involved in pain signaling. Crosstalk between Cdk5 and TGF-beta pathways affects nociceptive signaling: Our earlier studies on the characterization of the TGF-beta1-/- mouse phenotype confirmed TGF-beta1 as a key regulator of inflammation. TGF-beta1-/- mice develop a rapid wasting syndrome and die by 3-4 weeks of age. These mice display an excessive inflammatory response with massive infiltration of lymphocytes and macrophages into many organs, principally the heart, lungs, and salivary glands. TGF-beta1 is normally present at low levels in healthy adult CNS cells, but its level is rapidly up-regulated following injury and induces expression of several injury-related genes. TGF-beta1 is also known to promote the survival of neurons, although the mechanism is still not clear. TGF-beta1 has also been implicated in the pathology of Alzheimer's disease. TGF-beta1 over-expression in astrocytes can lead to excessive deposition of extracellular matrix components in the brain, resulting in neurological disease. Recent reports indicate that TGF-beta1 may participate in neuropathic and inflammatory pain; however, the molecular mechanisms underlying its involvement in pain signaling are still far from clear. Therefore, the main objective of our study was to explore possible crosstalk between Cdk5 and TGF-beta signaling pathways, and the influence of this crosstalk on inflammation-induced pain. Our studies revealed that the protein levels of Cdk5, p35, and p39 are reduced in the nervous tissues of TGF-beta1-/- mice, resulting in decreased Cdk5 activity. Moreover, TGF-beta1-/- mice showed decreased Cdk5-mediated phosphorylation of TRPV1 in the TG and DRG, with concomitant attenuated behavioral responses to noxious thermal stimulation. This was associated with decreased activity of PKC-delta, a known regulator of p35. Most importantly, we found that TGF-betaR1f/f; SNS-Cre mice also displayed decreased Cdk5 expression in DRGs along with hypoalgesia. In addition, TGF-beta1 treatment of rat neuroblastoma B104 cells increased Cdk5 activity, whereas treatment with SB-431542, an inhibitor of TGF-beta1 signaling, decreased Cdk5 activity. Treatment with TGF-beta1 potentiated capsaicin-induced Ca+2 influx in DRG primary cultures. These findings indicate that active crosstalk between TGF-beta and Cdk5 pathways regulate inflammation-induced pain signaling.